The goal of the Center for Reproductive Science and Medicine is to develop understanding of the mechanisms that govern normal and disordered function of the hypothalamic-pituitary-ovarian axis. We will continue to produce novel and important contributions to the reproductive sciences, integrating multidisciplinary clinical and basic research to facilitate and accelerate the translation of promising new discoveries into clinical medicine. We have chosen five innovative Research Projects, all with experienced, internationally renowned leaders. Four are renewing and one is new (Project II). Project I (Pamela L. Mellon, Project Leader, PL) will address the hormonal control of the gonadotropin [unreadable]-subunit genes in the pituitary, focusing on regulation by activin, GnRH, and steroid hormones. The emphasis will be on understanding the synergy and interdependence between these hormones in controlling transcription in model gonadotrope cells and genetically modified mice. Project II (Jerrold M. Olefsky, PL) will chart new territory in the role of estrogen in insulin insensitivity. Estrogenized women and female rodents are protected from fat-induced insulin resistance, whereas, males, and estrogen-deficient females are fully susceptible to these adverse effects of fat. A broad based, in vivo and in vitro approach is proposed to elucidate the mechanisms of fat induced insulin resistance and the protective effects of estrogens, using novel animal models, 3T3-L1 adipocytes, and ovarian granulosa cells [GCs]. Project III (Nicholas J.G. Webster, PL) will provide detailed molecular understanding of the signal transduction cascade of GnRH in the gonadotrope model cell system, focusing on pulsatile GnRH, the influence of steroids on GnRH signaling, and the role of GnRH in regulation of gonadotrope cell cycle. Project IV (Shunichi Shimasaki, PL) will capitalize on the finding that the oocyte controls follicle cytodifferentiation by paracrine mechanisms, addressing the role of estrogen in facilitating communication between the oocyte and the GC in maturing follicles. Project V (R. Jeffrey Chang, PL) will focus on the influence of gonadal steroids and insulin in the endocrine control of the ovarian GCs in vivo in normal women and patients with polycystic ovary syndrome, addressing fundamental mechanisms underlying PCOS. The only core will be the Administrative Core. The Administrative Core facilitates and supports all of the activities of the Center. It will also house the SCCPRR-wide Human Ovary Tissue Core. [unreadable] [unreadable]